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See corresponding editorial on page 787.

Coffee consumption and risk of chronic disease in the European Prospective Investigation into Cancer and Nutrition (EPIC)Germany study13
Anna Floegel, Tobias Pischon, Manuela M Bergmann, Birgit Teucher, Rudolf Kaaks, and Heiner Boeing
ABSTRACT Background: Early studies suggested that coffee consumption may increase the risk of chronic disease. Objective: We investigated prospectively the association between coffee consumption and the risk of chronic diseases, including type 2 diabetes (T2D), myocardial infarction (MI), stroke, and cancer. Design: We used data from 42,659 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)Germany study. Coffee consumption was assessed by self-administered foodfrequency questionnaire at baseline, and data on medically veried incident chronic diseases were collected by active and passive followup procedures. HRs and 95% CIs were calculated with multivariate Cox regression models and compared by competing risk analysis. Results: During 8.9 y of follow-up, we observed 1432 cases of T2D, 394 of MI, 310 of stroke, and 1801 of cancer as rst qualifying events. Caffeinated (HR: 0.94; 95% CI: 0.84, 1.05) or decaffeinated (HR: 1.05; 95% CI: 0.84, 1.31) coffee consumption (4 cups/d compared with ,1 cup/d; 1 cup was dened as 150 mL) was not associated with the overall risk of chronic disease. A lower risk of T2D was associated with caffeinated (HR: 0.77; 95% CI: 0.63, 0.94; P-trend 0.009) and decaffeinated (HR: 0.70; 95% CI: 0.46, 1.06; P-trend: 0.043) coffee consumption (4 cups/d compared with ,1 cup/d), but cardiovascular disease and cancer risk were not. The competing risk analysis showed no signicant differences between the risk associations of individual diseases. Conclusion: Our ndings suggest that coffee consumption does not increase the risk of chronic disease, but it may be linked to a lower risk of T2D. Am J Clin Nutr 2012;95:9018. INTRODUCTION

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cognitive function, and increased the heart rate (4). However, the effect of coffee consumption on chronic disease risk is still being debated. In randomized controlled trials it was observed that acute coffee ingestion caused an increase in blood pressure (5, 6) and led to an elevation in plasma concentrations of total and LDL cholesterol and homocysteine (79). Case-control studies reported a positive association (3, 10, 11), or a J-shaped relation (12), between coffee consumption and the risk of CVD4. Moreover, some studies reported an acute elevation in the risk of MI and stroke in the hour of coffee ingestion (13, 14). These ndings contributed to the belief that coffee is harmful (15), which is widespread among the general public and is also supported by current dietary recommendations that favor low to moderate coffee consumption. Prospective cohort studies, however, reported conicting results: some studies suggested a positive association between coffee consumption and risk of CVD (16, 17), whereas others reported no association (18, 19) or even an inverse association (2022). Most previous studies focused on the risk of coronary heart disease, and studies addressing stroke risk are even fewer. An inverse association between coffee consumption and risk of T2D has been suggested in a recent case-control study in the United States (23) and in many prospective cohort studies in Europe (2426), the United States (27, 28), and Japan (29). Studies investigating the association between coffee consumption and total cancer risk are rarely found in the literature because most studies focused on site-specic cancers. Some evidence exists that coffee may reduce the risk of liver, breast, and oral cavity/pharynx cancers (3033). In contrast,
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Coffee is among the most popular nonalcoholic beverages and is one of the most valuable export commodities in the world (1). In 2007, the top coffee consuming country was Finland with 12 kg per capita. In Germany, the average coffee consumption in 2007 was 6.4 kg per capita, whereas in the United States it was 4.2 kg per capita (2). After removal of the esh from the coffee cherries, the seeds are roasted and develop their unique bitter aroma. Coffee is a complex chemical mixture, and its most abundant components are chlorogenic acid and caffeine followed by other polyphenols and methylxanthines, carbohydrates, lipids, nitrogenous compounds, nicotinic acid, potassium, and magnesium to name a few (3). Besides its culinary value, coffee has long been suggested to affect human health and disease (3). In the late 16th century, British doctors observed that coffee accelerated digestion, improved

From the Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany (AF, TP, MMB, and HB); the Molecular Epidemiology Group, Max Delbruck Center for Molec ular Medicine Berlin-Buch, Germany (TP); and the Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany (BT and RK). 2 Supported by the Federal Ministry of Science, Germany (grant 01 EA 9401), the European Union (grant SOC 95 201408 05F02), and the German Cancer Aid (grant 70-2201-Bo2). 3 Address correspondence and reprint requests to A Floegel, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. E-mail: anna.oegel@dife.de. 4 Abbreviations used: CVD, cardiovascular disease; EPIC, European Prospective Investigation into Cancer and Nutrition; FFQ, food-frequency questionnaire; MI, myocardial infarction; T2D, type 2 diabetes. Received July 18, 2011. Accepted for publication December 29, 2011. First published online February 15, 2012; doi: 10.3945/ajcn.111.023648.

Am J Clin Nutr 2012;95:9018. Printed in USA. 2012 American Society for Nutrition
Supplemental Material can be found at: http://www.ajcn.org/content/suppl/2012/03/22/95.4.901.DC1. html

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results from case-control studies suggest that coffee consumption may increase the risk of pancreatic, bladder, ovarian, and prostate cancer but the evidence is considered insufcient (3, 33, 34). With such contrasting ndings, the public debate about reducing the risk of one disease only to increase the risk of another by drinking coffee is very much alive. From a public health perspective, it is most relevant to investigate whether coffee consumption affects morbidity from major chronic diseases and whether individual disease risks are competing with each other to optimally translate evidence-based recommendations. Furthermore, the relation between coffee consumption and risk of MI and stroke and total cancer risk is not resolved and deserves large-scale prospective investigations. In particular, more studies in European cohorts are desirable to support evidence from US cohorts (35). In addition, previous studies did not generally differentiate between caffeinated and decaffeinated coffee (36). Therefore, the current study aimed to prospectively investigate the association between caffeinated and decaffeinated coffee consumption and risk of chronic disease, including T2D, MI, stroke, and cancer in the EPIC-Germany cohort.

consume coffee with caffeine in the past? and How frequently did you consume coffee without caffeine in the past? Ten frequency categories were provided, ranging from never to less than 1/mo to 5 times/d or more. In addition, the usual portion size was assessed with categories ranging from 0.5 cups to 3 cups (1 cup was dened as 150 mL). From the frequency and portion size, the usual consumption of caffeinated and decaffeinated coffee was estimated.
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Ascertainment of incident chronic diseases Incident cases of T2D, MI, stroke, and cancer were identied by participants self-report of the disease occurrence, disease-relevant medication, or change in diet or cause of death information. Potential incident diseases were further veried by contacting the treating physician and/or clinic to obtain medical records or via linkage to cancer and hospital registries (39). The diseases were coded in accordance with the International Statistical Classication of Diseases, 10th Revision (ICD-10) (40), criteria: E11 for T2D; I21 for MI; I60, I61, I63, and I64 for stroke; and C00-C97 for cancer (except C44: nonmelanoma skin cancer). In the current analysis, in case of multimorbidity, only the rst occurring incident event was counted. Statistical analysis Habitual caffeinated and decaffeinated coffee consumption were considered as exposure variables. The population was divided into 5 coffee consumption categories (,1 cup/d, 1 to ,2 cups/d, 2 to ,3 cups/d, 3 to ,4 cups/d, and 4 cups/d). The categories chosen agree well with plausible cutoff points of coffee consumption in other studies (41). Descriptive statistics of the covariates were ageand sex-adjusted and reported across coffee-consumption categories as arithmetic means 6 SEs for continuous variables or as percentages for categorical variables. The primary endpoint for this analysis was dened as the rst incident event occurring for T2D, MI, stroke, or cancer, whichever came rst. Cox proportional hazards analysis was used to estimate multivariableadjusted HRs as a measure of the RR and 95% CIs, with age as the primary time-dependent variable (entry and exit time of each participant dened as the age at recruitment and age at rst event of T2D, MI, stroke, cancer, or censoring, respectively). Furthermore, the disease-specic HRs for T2D, MI, stroke, and cancer across categories of coffee consumption were estimated. Coffee consumers of ,1 cup/d were used as the reference group. We calculated 3 different multivariate models for each exposure and outcome. All models were stratied by integers of age at recruitment to be less sensitive to violation of the proportional hazards assumption. Model 1 was the crude model and stratied by age at recruitment and center (Potsdam or Heidelberg) and adjusted for sex. Model 2 was additionally adjusted for classic risk factors, particularly smoking (nonsmokers; smoking intensity: ,15, 1524, or 25 cigarettes/d, other smoking; former smokers: gave up smoking 10, 1120, or .20 y previously; smoking duration: 10, 1120, 2130 y, 3140 y, or .40 y), alcohol consumption (nonconsumers; women: .06, .612, or .12 g/d; men: .012, .1224, or .24 g/d), physical activity (average of cycling and sports during summer and winter; in h/wk), education (none to primary school, technical to secondary school, or higher education including university), employment

SUBJECTS AND METHODS

Study population The EPIC study is a multicenter prospective cohort study in 10 European countries that aims to investigate the associations between diet, lifestyle, and chronic disease risk. In Germany, there are 2 study centers, which are located in Potsdam and Heidelberg. Adults aged mainly between 35 and 65 y were recruited from the general population in Potsdam, Heidelberg, and surrounding areas with response rates of 22.7% in Potsdam and 38.3% in Heidelberg (37, 38). A total of 53,088 adults (30,255 women and 22,833 men) consented to participate during the recruitment examination, which took place between 1994 and 1998. At baseline, study participants underwent an examination that included anthropometric and blood pressure measurements and an interview on medical history, including prevalent diseases. A self-administered questionnaire on sociodemographic and lifestyle factors and an FFQ were also completed. After baseline, follow-up questionnaires were administered every 23 y to identify incident cases of chronic diseases, including T2D, MI, stroke, and cancer. For the current analysis, we considered the data until the fourth follow-up period. Written informed consent was obtained from all study participants a priori. The study was approved by the ethics committees of the Medical Society of the State of Brandenburg and of the faculty of Medicine, Heidelberg University. For the current analysis, we excluded participants with missing information on coffee consumption (n = 17), those with selfreported chronic diseases (T2D, MI, stroke, or cancer) at baseline (n = 5536) or with unknown disease status (n = 2392), those with missing information on lifestyle factors and other covariates (n = 1830), and those who never completed a follow-up questionnaire (n = 654). Coffee consumption The EPIC-Germany participants were inquired about their habitual consumption of caffeinated coffee and decaffeinated coffee in the self-administered semi-quantitative FFQ at baseline. In particular, the 2 items were as follows: How frequently did you

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(yes or no), vitamin and mineral supplement use (during past 4 wk: yes or no), total energy intake (kcal/d), and tea intake (cups/d). Model 3 included the covariates of model 2 with additional adjustment for risk factors that could be considered intermediates, particularly BMI (in kg/m2), waist-to-hip ratio (continuous), and prevalent hypertension (at least one of the following: systolic blood pressure 140 mmHg, diastolic blood pressure 90 mmHg, blood pressurelowering medication, or self-reported: yes or no). In addition, in models 2 and 3, caffeinated and decaffeinated coffee consumption (cups/d) was mutually adjusted. We also calculated continuous models because a dose-dependent effect was assumed. Furthermore, the signicance of linear trends across the caffeinated coffee consumption categories was tested by assigning each participant the median of the category and modeling this value as a continuous variable. In addition, we conducted a competing risk analysis for Cox regression based on multivariate model 3 and used the likelihood ratio test to compare the disease-specic risk associations (42, 43). Interactions were tested between coffee consumption (continuous), chronic disease risk, and the covariates age, sex, center (Potsdam or Heidelberg), alcohol intake (categorical), smoking status (categorical), BMI (30, yes or no), and hypertension (yes or no). Models with and without multiplicative interaction terms were compared by using the likelihood ratio test. If an interaction was observed, a stratied analysis was conducted. For sensitivity analysis, we calculated disease-specic HRs, including subjects with any prevalent chronic disease, except the disease under investigation. Furthermore, we conducted the analysis excluding all nonconsumers of coffee from the reference group, excluding tea

consumers of .1 cup/d, and excluding all cases that occurred during the rst 2 y of follow-up. The level of statistical signicance was set at P , 0.05 for 2-sided testing. All analyses were performed with SAS statistical software (release 9.1; SAS Institute Inc).
RESULTS

The nal study population comprised 42,659 EPIC-Germany participants (58.5% women) with a mean age of 49.7 y and mean caffeinated and decaffeinated coffee intakes of 2.7 and 0.3 cups/d, respectively. In this population, coffee consumption was distributed as follows: 72.6% reported to consume caffeinated coffee only, 4.5% reported to consume decaffeinated coffee only, 18.6% reported to consume both, and 4.3% reported to consume neither coffee type. The percentage of current smokers proportionally increased with caffeinated coffee consumption from 14.4% to 30.2% in a comparison of ,1 to 4 cups/d (Table 1). With increasing caffeinated coffee consumption, decaffeinated coffee and tea consumption decreased on a population level, and alcohol consumption increased by trend. With increasing decaffeinated coffee consumption, the proportion of current smokers increased from 21.5% to 35.6%, and the number of cigarettes smoked per day increased from 13.9 to 17.0 in a comparison of ,1 to 4 cups/d, respectively (Table 2). Decaffeinated coffee consumers were less likely to have a university degree and were more likely to have a diagnosis of hypertension. The consumption of caffeinated and decaffeinated coffee was not associated with the overall risk of chronic disease in the crude model as well as in multivariate model 2 (including known risk

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TABLE 1 Baseline characteristics of the EPIC-Germany population (n = 42,659) according to caffeinated coffee consumption1 Caffeinated coffee consumption ,1 cup/d No. of subjects Women (%)2 Age (y)2 BMI (kg/m2) Waist circumference (cm) Waist-to-hip ratio Currently employed (%) University degree (%) Current smokers (%) Cigarettes smoked (no./d)3 Former smokers (%) Sports (h/wk) Watching television (h/wk) Total energy intake (kcal/d) Alcohol intake from beverages (g/d) Decaffeinated coffee (cups/d) Caffeinated tea (cups/d) Taking vitamin supplement (%) Taking mineral supplement (%) Prevalent hypertension (%) Systolic blood pressure (mm Hg)4 Diastolic blood pressure (mm Hg)4
1

1 to ,2 cups/d 3860 58.9 49.2 6 8.5 25.8 6 0.06 86.0 6 0.17 0.85 6 0.00 74.3 36.9 14.9 11.7 6 0.4 33.3 3.4 6 0.1 12.4 6 0.1 1970 6 11 15.3 6 0.3 0.27 6 0.02 1.1 6 0.0 20.3 15.5 38.5 134.9 6 0.4 87.1 6 0.3

2 to ,3 cups/d 10,617 62.8 49.8 6 8.7 25.8 6 0.04 85.8 6 0.10 0.85 6 0.00 73.3 36.0 16.8 12.0 6 0.2 34.7 3.4 6 0.0 12.8 6 0.1 2001 6 6 15.9 6 0.2 0.15 6 0.01 0.73 6 0.02 18.8 13.4 38.2 136.0 6 0.2 87.6 6 0.2

3 to ,4 cups/d 7356 57.4 49.0 6 8.2 25.8 6 0.05 85.8 6 0.12 0.85 6 0.00 77.8 36.1 26.8 13.8 6 0.2 33.2 3.2 6 0.0 12.7 6 0.1 2045 6 8 16.8 6 0.2 0.10 6 0.01 0.54 6 0.01 19.5 14.4 35.4 134.3 6 0.3 86.8 6 0.2

4 cups/d 12,137 56.9 50.2 6 8.4 26.2 6 0.04 86.8 6 0.09 0.85 6 0.00 73.2 33.0 30.2 15.7 6 0.2 31.0 3.2 6 0.0 13.5 6 0.1 2177 6 6 16.0 6 0.2 0.15 6 0.01 0.55 6 0.01 18.8 13.7 34.9 134.5 6 0.2 86.8 6 0.1

8689 56.1 49.9 6 8.6 25.8 6 0.04 86.4 6 0.11 0.86 6 0.00 69.0 34.6 14.4 13.2 6 0.3 32.2 3.8 6 0.0 12.3 6 0.1 2005 6 7 13.5 6 0.2 0.75 6 0.01 1.8 6 0.0 22.1 16.6 37.6 133.4 6 0.3 85.5 6 0.2

All values are age- and sex-adjusted means 6 SEs or percentages across coffee consumption categories, except where otherwise noted. One cup was dened as 150 mL. EPIC, European Prospective Investigation into Cancer and Nutrition. 2 Unadjusted means 6 SDs or percentages. 3 In current smokers only. 4 n = 18,372.

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factors) and model 3 (which considered possible intermediates) (Tables 3 and 4). For further analysis, model 3 was our model of choice. RRs of single endpoints showed that caffeinated coffee consumption was inversely associated with T2D risk, because consumption of 4 cups/d was associated with a 23% lower risk of T2D compared with ,1 cup/d, but was not related to the other endpoints. Consumption of decaffeinated coffee was inversely associated with T2D risk (P-trend: 0.043) and was not associated with the other endpoints. However, in the highest category of 4 cups/d compared with ,1 cup/d, decaffeinated coffee consumption was positively associated with MI risk (Table 4). The competing risk analysis showed that there was no signicant difference between the RR associations of the individual diseases (see Table S1 under Supplemental data in the online issue). A signicant interaction between caffeinated coffee consumption, smoking status, and T2D risk was found (P = 0.015). The stratied analysis showed the inverse association for T2D risk to be specic for nonsmokers at baseline (see Figure S1 under Supplemental data in the online issue). No association with T2D risk was observed among current smokers. We further observed a signicant interaction between decaffeinated coffee consumption, prevalent hypertension, and T2D risk (P = 0.0001), which suggests that persons with normal blood pressure may not benet from decaffeinated coffee consumption in respect of T2D risk. We conducted several sensitivity analyses (data not shown). The results were not markedly altered when we rst, included subjects with prevalent chronic diseases at baseline; second, excluded all nonconsumers of coffee from the reference group; or third, con-

ducted the analysis among those with low exposure to caffeine from tea. Last, when we excluded all cases that occurred during the rst 2 y of follow-up, the association between high decaffeinated coffee consumption and MI risk was no longer observed, and a stronger inverse association was found between decaffeinated coffee consumption and T2D risk. The proportional hazard assumption was met.
DISCUSSION

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Despite a general belief that coffee may be harmful, the current study found no association between coffee consumption and the risk of chronic disease. Current dietary guidelines recommend moderate coffee consumption; the American Heart Association even recommends to restrict caffeinated coffee consumption to 12 cups/d (44). They most likely refer to early epidemiologic studies that found a positive association between coffee consumption and CVD risk. In contrast to current dietary recommendations, we observed that coffee consumption was not associated with risk of CVD, but that high coffee consumption was associated with lower T2D risk. An inverse association between coffee consumption and T2D risk has been reported in previous studies across continents (26 28, 40, 45). In accordance to our results, Huxley et al (40) found that T2D risk was reduced by 24% when caffeinated coffee consumption of 35 cups/d was compared with 2 cups/d in their meta-analysis; similar results were observed for decaffeinated coffee consumption. In addition, our ndings suggest that the association between decaffeinated coffee and risk of

TABLE 2 Baseline characteristics of the EPIC-Germany population (n = 42,659) according to decaffeinated coffee consumption1 Decaffeinated coffee consumption ,1 cup/d No. of subjects Women (%)2 Age (y)2 BMI (kg/m2) Waist circumference (cm) Waist-to-hip ratio Currently employed (%) University degree (%) Current smokers (%) Cigarettes smoked (no./d)3 Former smokers (%) Sports (h/wk) Watching television (h/wk) Total energy intake (kcal/d) Alcohol intake from beverages (g/d) Caffeinated coffee (cups/d) Caffeinated tea (cups/d) Taking vitamin supplement (%) Taking mineral supplement (%) Prevalent hypertension (%) Systolic blood pressure (mm Hg)4 Diastolic blood pressure (mm Hg)4
1

1 to ,2 cups/d 1273 62.9 50.3 6 8.6 26.2 6 0.1 86.6 6 0.3 0.85 6 0.00 69.0 25.6 19.1 14.2 6 0.6 32.0 3.7 6 0.1 13.0 6 0.2 2056 6 19 12.9 6 0.5 1.6 6 0.1 0.67 6 0.05 21.8 15.6 39.0 133.8 6 0.7 85.8 6 0.4

2 to ,3 cups/d 1390 64.5 51.6 6 8.6 26.8 6 0.1 88.3 6 0.3 0.86 6 0.00 65.0 24.0 19.0 14.1 6 0.6 33.4 3.7 6 0.1 13.6 6 0.2 2026 6 18 13.8 6 0.5 1.3 6 0.1 0.60 6 0.05 20.8 13.8 42.6 136.3 6 0.7 87.2 6 0.4

3 to ,4 cups/d 486 60.5 51.1 6 8.3 26.8 6 0.2 88.8 6 0.5 0.87 6 0.00 71.0 25.6 28.2 14.6 6 0.9 31.7 3.7 6 0.1 13.9 6 0.4 2038 6 30 15.2 6 0.9 1.1 6 0.1 0.65 6 0.08 21.1 17.1 40.0 133.5 6 1.1 85.3 6 0.7

4 cups/d 882 59.9 50.6 6 8.2 27.4 6 0.1 89.6 6 0.3 0.87 6 0.00 67.0 15.7 35.6 17.0 6 0.6 32.3 3.8 6 0.1 15.1 6 0.3 2178 6 22 14.2 6 0.6 1.7 6 0.1 0.68 6 0.06 18.4 13.9 40.4 133.6 6 0.8 85.9 6 0.5

38,628 58.0 49.6 6 8.5 25.9 6 0.0 86.0 6 0.1 0.85 6 0.00 74.0 36.2 21.5 13.9 6 0.1 32.8 3.3 6 0.0 12.8 6 0.0 2055 6 3 15.7 6 0.1 2.9 6 0.0 0.91 6 0.01 19.6 14.5 36.3 134.7 6 0.1 86.8 6 0.1

All values are age- and sex-adjusted means 6 SEs or percentages across coffee consumption categories, except where otherwise noted. One cup was dened as 150 mL. EPIC, European Prospective Investigation into Cancer and Nutrition. 2 Unadjusted means 6 SDs or percentages. 3 In current smokers only. 4 n = 18,372.

COFFEE CONSUMPTION AND RISK OF CHRONIC DISEASE


TABLE 3 HRs (and 95% CIs) for the association between caffeinated coffee consumption and incident chronic diseases in EPIC-Germany (n = 42,659)1 Caffeinated coffee consumption ,1 cup/d No. of subjects/person-years Overall chronic disease No. of cases Model 1 Model 2 Model 3 Type 2 diabetes No. of cases Model 1 Model 2 Model 3 Combined CVD No. of cases Model 1 Model 2 Model 3 Myocardial infarction No. of cases Model 1 Model 2 Model 3 Stroke No. of cases Model 1 Model 2 Model 3 Cancer No. of cases Model 1 Model 2 Model 3 8689/78,974 871 1.00 1.00 1.00 319 1.00 1.00 1.00 148 1.00 1.00 1.00 88 1.00 1.00 1.00 60 1.00 1.00 1.00 404 1.00 1.00 1.00 1 to ,2 cups/d 3860/34,341 336 0.96 (0.83, 1.11) 0.97 (0.84, 1.13) 0.99 (0.85, 1.14) 137 0.92 (0.72, 1.16) 0.93 (0.73, 1.19) 0.89 (0.69, 1.16) 50 0.92 (0.64, 1.32) 0.93 (0.64, 1.35) 0.94 (0.64, 1.36) 24 0.65 (0.39, 1.10) 0.61 (0.36, 1.06) 0.62 (0.36, 1.07) 26 1.35 (0.80, 2.27) 1.35 (0.79, 2.31) 1.38 (0.81, 2.38) 149 0.99 (0.81, 1.22) 1.01 (0.82, 1.25) 1.01 (0.82, 1.25) 2 to ,3 cups/d 10,617/93,272 979 1.02 (0.92, 1.13) 1.03 (0.92, 1.15) 1.03 (0.92, 1.15) 374 0.93 (0.78, 1.11) 0.92 (0.76, 1.11) 0.92 (0.76, 1.13) 164 1.07 (0.82, 1.39) 1.08 (0.82, 1.42) 1.07 (0.81, 1.42) 79 0.87 (0.61, 1.24) 0.89 (0.61, 1.29) 0.86 (0.59, 1.25) 85 1.41 (0.95, 2.11) 1.35 (0.89, 2.07) 1.39 (0.90, 2.12) 441 1.06 (0.91, 1.23) 1.08 (0.92, 1.26) 1.08 (0.92, 1.27) 3 to ,4 cups/d 7356/65,881 627 0.96 (0.85, 1.08) 0.93 (0.82, 1.06) 0.95 (0.84, 1.08) 210 0.85 (0.70, 1.04) 0.83 (0.67, 1.02) 0.82 (0.65, 1.02) 120 1.13 (0.85, 1.49) 1.00 (0.74, 1.36) 1.02 (0.75, 1.38) 70 1.07 (0.74, 1.55) 0.92 (0.61, 1.37) 0.91 (0.61, 1.36) 50 1.21 (0.78, 1.88) 1.07 (0.67, 1.73) 1.13 (0.70, 1.82) 297 0.97 (0.82, 1.15) 0.98 (0.82, 1.18) 0.98 (0.82, 1.18) 4 cups/d 12,137/107,290 1124 0.99 (0.89, 1.09) 0.93 (0.84, 1.04) 0.94 (0.84, 1.05) 392 0.89 (0.75, 1.06) 0.81 (0.67, 0.98) 0.77 (0.63, 0.94) 222 1.25 (0.98, 1.59) 1.07 (0.82, 1.40) 1.10 (0.84, 1.44) 133 1.19 (0.87, 1.63) 0.98 (0.69, 1.39) 0.98 (0.69, 1.39) 89 1.36 (0.93, 2.01) 1.20 (0.78, 1.83) 1.28 (0.83, 1.95) 510 0.97 (0.83, 1.12) 0.97 (0.82, 1.14) 0.97 (0.83, 1.14) P-trend

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Per cup/d

0.735 0.149 0.206

1.01 (0.99, 1.02) 0.99 (0.97, 1.01) 0.99 (0.97, 1.01)

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0.134 0.019 0.009

1.00 (0.98, 1.03) 0.99 (0.96, 1.02) 0.98 (0.95, 1.01)

0.043 0.569 0.435

1.04 (1.00, 1.07) 1.00 (0.96, 1.04) 1.00 (0.96, 1.04)

0.114 0.760 0.765

1.04 (0.99, 1.09) 0.99 (0.94, 1.04) 0.99 (0.94, 1.04)

0.207 0.708 0.488

1.03 (0.98, 1.09) 1.00 (0.94, 1.06) 1.01 (0.95, 1.07)

0.558 0.553 0.573

0.99 (0.97, 1.02) 0.99 (0.97, 1.02) 0.99 (0.97, 1.02)

1 HRs and 95% CIs were calculated by using multivariate Cox proportional hazard regression. Model 1: stratied by age at recruitment (y) and center (Potsdam/Heidelberg) and adjusted for sex. Model 2: adjusted as for model 1 with additional adjustment for smoking (status, duration, and intensity), alcohol intake (nonconsumers; women: .06, .612, or .12 g/d; men: .012, .1224, or .24 g/d), physical activity (average of cycling and sports during summer and winter; in h/wk), education (none to primary school, technical to secondary school, or higher education including university), employment (yes or no), vitamin and mineral supplement use during past 4 wk (yes or no), total energy intake (kcal/d), tea intake (cups/d), and decaffeinated coffee intake (cups/d). Model 3: adjusted as for model 2 with additional adjustment for BMI (kg/m2), waist-to-hip ratio, and prevalent hypertension (yes or no). One cup was dened as 150 mL. CVD, cardiovascular disease; EPIC, European Prospective Investigation into Cancer and Nutrition.

T2D may differ between subjects with or without prevalent hypertension. We furthermore observed an interaction between caffeinated coffee consumption and smoking. Among nonsmokers, an inverse association was found between caffeinated coffee consumption and risk of T2D; among current smokers, this dosedependent inverse association was not observed. Because smoking is an established risk factor for T2D, the adverse effects of smoking may cancel out the potential benets of coffee consumption on T2D risk. Thus, we speculate that smokers may not benet from coffee consumption in respect of T2D risk. We found no association between coffee consumption and CVD risk, including MI and stroke, after multivariate adjustment. An early meta-analysis of case-control studies found a positive association between coffee consumption and MI risk, but only few studies adjusted for smoking or alcohol intake (10). Results from prospective cohort studies are inconsistent. Some studies reported that coffee consumption was independently associated with higher risk of MI (16, 17), whereas other studies and recent meta-analyses support evidence that there is no harmful relation

between coffee consumption and CVD mortality (4648), risk of coronary heart disease (19, 49, 50), or specically MI risk (51). In fact, more recent prospective cohort studies reported an inverse association between coffee consumption and risk of stroke (20 22). In our crude model, we observed a positive association between both caffeinated and decaffeinated coffee consumption and CVD risk. This is most likely explained by the unfavorable lifestyle of high coffee consumers, especially in respect of smoking, because smoking itself represents a strong risk factor for CVD. In line with our ndings, it was previously observed that the association between coffee consumption and CVD risk may be confounded by smoking (52, 53). We observed a positive association between decaffeinated coffee consumption and MI risk, in the highest category of 4 cups/d compared with ,1 cup/d. An Italian case-control study found a positive association between decaffeinated coffee consumption and MI risk (54), whereas other studies did not nd such associations (55). Because decaffeinated coffee consumption was not common in our population, our results have to be interpreted with caution. A

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TABLE 4 HRs (and 95% CIs) for the association between decaffeinated coffee consumption and incident chronic diseases in EPIC-Germany (n = 42,659)1 Decaffeinated coffee consumption ,1 cup/d No. of subjects/person-years Overall chronic disease No. of cases Model 1 Model 2 Model 3 Type 2 diabetes No. of cases Model 1 Model 2 Model 3 Combined CVD No. of cases Model 1 Model 2 Model 3 Myocardial infarction No. of cases Model 1 Model 2 Model 3 Stroke No. of cases Model 1 Model 2 Model 3 Cancer No. of cases Model 1 Model 2 Model 3 38,628/343,062 3493 1.00 1.00 1.00 1262 1.00 1.00 1.00 621 1.00 1.00 1.00 342 1.00 1.00 1.00 279 1.00 1.00 1.00 1610 1.00 1.00 1.00 1 to ,2 cups/d 1273/11,500 136 1.18 (0.97, 1.42) 1.13 (0.93, 1.37) 1.12 (0.92, 1.36) 46 1.14 (0.82, 1.58) 1.04 (0.74, 1.45) 0.97 (0.68, 1.39) 28 1.47 (0.95, 2.26) 1.39 (0.89, 2.17) 1.41 (0.91, 2.21) 17 1.71 (0.98, 2.96) 1.58 (0.88, 2.83) 1.59 (0.89, 2.82) 11 1.17 (0.58, 2.35) 1.15 (0.56, 2.35) 1.15 (0.56, 2.35) 62 1.11 (0.84, 1.47) 1.13 (0.85, 1.49) 1.12 (0.85, 1.49) 2 to ,3 cups/d 1390/12,778 154 1.10 (0.92, 1.32) 1.07 (0.89, 1.28) 0.97 (0.81, 1.17) 71 1.51 (1.15, 2.00) 1.42 (1.08, 1.88) 1.11 (0.84, 1.48) 27 1.10 (0.71, 1.71) 1.06 (0.68, 1.66) 1.01 (0.64, 1.58) 14 1.42 (0.81, 2.49) 1.38 (0.77, 2.46) 1.28 (0.72, 2.29) 13 0.86 (0.44, 1.67) 0.84 (0.43, 1.66) 0.82 (0.42, 1.61) 56 0.83 (0.62, 1.11) 0.82 (0.61, 1.10) 0.82 (0.61, 1.10) 3 to ,4 cups/d 486/4549 45 0.93 (0.68, 1.28) 0.88 (0.64, 1.21) 0.81 (0.59, 1.12) 18 1.06 (0.64, 1.78) 0.96 (0.57, 1.61) 0.70 (0.41, 1.19) 6 0.76 (0.33, 1.76) 0.73 (0.32, 1.69) 0.73 (0.32, 1.67) 4 0.99 (0.35, 2.75) 0.93 (0.34, 2.58) 0.91 (0.33, 2.50) 2 0.52 (0.12, 2.18) 0.51 (0.12, 2.18) 0.51 (0.12, 2.17) 21 0.92 (0.58, 1.45) 0.89 (0.56, 1.42) 0.89 (0.56, 1.42) 4 cups/d 882/7868 109 1.31 (1.06, 1.63) 1.17 (0.94, 1.45) 1.05 (0.84, 1.31) 35 1.16 (0.78, 1.72) 0.94 (0.63, 1.40) 0.70 (0.46, 1.06) 22 1.66 (1.03, 2.65) 1.43 (0.88, 2.32) 1.36 (0.84, 2.20) 17 2.26 (1.30, 3.93) 2.03 (1.15, 3.58) 1.90 (1.08, 3.34) 5 0.90 (0.36, 2.27) 0.79 (0.31, 2.01) 0.76 (0.30, 1.93) 52 1.30 (0.96, 1.76) 1.27 (0.93, 1.73) 1.27 (0.94, 1.74) P-trend Per cup/d

0.741 0.285 0.620

1.05 (1.02, 1.08) 1.02 (0.99, 1.06) 1.00 (0.97, 1.04)

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0.138 0.007 0.043

1.05 (1.00, 1.11) 1.01 (0.96, 1.07) 0.95 (0.90, 1.01)

0.043 0.338 0.300

1.07 (1.00, 1.14) 1.04 (0.97, 1.10) 1.03 (0.96, 1.10)

0.114 0.597 0.575

1.12 (1.04, 1.20) 1.09 (1.01, 1.17) 1.08 (1.00, 1.16)

0.207 0.476 0.403

0.95 (0.83, 1.10) 0.94 (0.81, 1.08) 0.93 (0.80, 1.07)

0.558 0.973 0.950

1.03 (0.99, 1.08) 1.03 (0.98, 1.08) 1.03 (0.98, 1.08)

1 HRs and 95% CIs were calculated by using multivariate Cox proportional hazard regression. Model 1: stratied by age at recruitment (y) and center (Potsdam/Heidelberg) and adjusted for sex. Model 2: adjusted as for model 1 with additional adjustment for smoking (status, duration, and intensity), alcohol intake (nonconsumers; women: .06, .612, or .12 g/d; men: .012, .1224, or .24 g/d), physical activity (average of cycling and sports during summer and winter; in h/wk), education (none to primary school, technical to secondary school, or higher education including university), employment (yes or no), vitamin and mineral supplement use during past 4 wk (yes or no), total energy intake (kcal/d), tea intake (cups/d), and caffeinated coffee intake (cups/d). Model 3: adjusted as for model 2 with additional adjustment for BMI (kg/m2), waist-to-hip ratio, and prevalent hypertension (yes or no). One cup was dened as 150 mL. CVD, cardiovascular disease; EPIC, European Prospective Investigation into Cancer and Nutrition.

plausible explanation for this association is not apparent, because caffeine is considered the relevant factor for a possible positive association between coffee consumption and MI risk. We may not have been able to account for all possible confounders associated with high decaffeinated coffee consumption, eg, participants who are already at high CVD risk may choose to substitute caffeinated coffee with decaffeinated coffee. Therefore, we speculate that residual confounding may cause the association we observed between high decaffeinated coffee consumption and increased MI risk. This assumption is supported by the fact that when we excluded all cases that occurred during the rst 2 y of follow-up in the sensitivity analysis, the positive association between decaffeinated coffee consumption and MI risk was attenuated and no longer signicant. To summarize, previous studies and our ndings support the concept that there may be no harmful effect of coffee on CVD risk per se. Insufcient consideration of important CVD risk factors that are linked to coffee consumption (particularly smoking) may be

responsible for the earlier belief that coffee consumption increased CVD risk. In previous studies, coffee consumption has been found to be associated with reduced or increased cancer risk, depending on the type of cancer and study design. Studies investigating the effect of coffee consumption on total cancer risk are rare. A recent metaanalysis including data from 59 prospective cohort studies found a 3% reduction in overall cancer risk per cup of coffee consumed (56). In our study, there was no association between caffeinated or decaffeinated coffee consumption and total cancer risk. The strength of our study was that we conducted a rst-event analysis taking into account 4 major chronic diseases to determine the overall effect of coffee consumption on chronic disease risk and additionally tested whether the risk associations may compete with each other. Furthermore, we considered caffeinated and decaffeinated coffee as an exposure. We also included a large subsample of the German population from 2 different regions. Last, the prospective design of our study allowed us to investigate time-

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dependent exposure-disease associations. However, our study also had some limitations. Coffee consumption was assessed by FFQ at the time of recruitment and relied on participants self-report. Nevertheless, data from the Nurses Health Study suggest that coffee consumption is very stable in an individual over time, because it showed the best reproducibility among all food items in repeated measures (57). As previously described (58), ltering may alter coffees metabolic effects. The method of coffee preparation was not assessed in our study population, and we were therefore not able to study whether the association between coffee consumption and chronic disease risk depends on the ltering of coffee. In Germany, ltering is the traditional method of coffee preparation (59); thus, our ndings most likely apply to ltered coffee. Because of the small number of decaffeinated coffee consumers in our population, there were also fewer cases for some of the disease endpoints. Hence, the associations found will benet from further investigation. Our study sample was drawn from the general population; however, because the response rates were low, it overrepresents health-conscious people with higher socioeconomic status (37). Because this was an observational study, we can only show associations. Whether these associations represent true causal effects has to be conrmed in future studies. Last, it has to be noted that we were primarily interested in investigating the association between coffee consumption and risk of major chronic diseases. We cannot exclude the possibility that coffee consumption may be associated with risk of certain disease subtypes, eg, site-specic cancers. This should be the focus of future studies. In conclusion, our study does not support the hypothesis that coffee is detrimental to human health. In fact, we observed an inverse association between coffee consumption and T2D risk, which challenges the evidence base for current recommendations. We speculate that the unfavorable lifestyle characteristics of high coffee consumers, especially with respect to smoking, may be responsible for the positive association between coffee consumption and CVD risk, which was reported in early studies. In addition, coffee and cigarettes may be an unfavorable combination, which requires further investigation.
We thank all of the EPIC-Germany study participants. The authors responsibilities were as followsAF, TP, and HB: study concept and design; MMB, BT, RK, and HB: data acquisition; AF: data analysis and interpretation and draft of the manuscript; and TP, MMB, BT, RK, and HB: data interpretation, intellectual input, and critical review of the manuscript. All authors read and approved the nal version of the manuscript. None of the authors declared a conict of interest.

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